PROJECT SUMMARY Children of women who smoke during pregnancy exhibit higher-order auditory-cognitive deficits, but the relationship, if any, between developmental chronic nicotine exposure (CNE) and subsequent auditory deficits is unclear. Results from a newly-developed animal model indicate that CNE during development produces auditory-cognitive deficits, and reveal a potential cellular link: functional impairment of nicotinic acetylcholine receptors (nAChRs) in primary auditory cortex (A1). Studies also show that nAChRs normally enhance cortical processing in two ways: i) by increasing sensitivity to characteristic frequency (CF) stimuli, and ii) by reducing sensitivity to spectrally-distant stimuli. In other words, receptive fields become more sharply tuned. Preliminary studies on the auditory thalamocortical brain slice reveal a surprising cellular basis of the first effect: nAChRs facilitate responsiveness in A1 by enhancing axon excitability in thalamocortical relay neurons. This novel mechanism of nAChR function implies that a neurotransmitter (in this case acetylcholine) can regulate myelinated thalamocortical axons. The proposed studies test the hypothesis that nAChRs enhance thalamocortical axon excitability to increase sensitivity to CF stimuli, and excite cortical interneurons to reduce responses to spectrally-distant stimuli. The studies will exploit the thalamocortical brain slice to examine cellular mechanisms by which nAChRs differentially regulate thalamocortical and intracortical transmission. Parallel in vivo studies will determine how cellular mechanisms identified in the slice contribute to acoustic processing in the intact animal. Finally, the mechanism by which neonatal CNE produces lasting deficits in nAChR function will be examined by determining how CNE alters intracellular signal transduction activated by nicotine. The long-term goal of the proposed studies is an understanding of nAChR function in A1 and its disruption by CNE, which, in turn, may guide therapies for CNE-induced deficits. PROJECT NARRATIVE The effect of tobacco smoke on fetal brain development is a major public health issue, since most women who smoke continue to do so during pregnancy. Recent animal studies have confirmed a causal role for nicotine in producing long-lasting auditory-cognitive impairments, and the proposed studies will continue this work to identify the underlying cellular and molecular mechanisms, with the long-term goal of developing therapies to treat nicotine-induced cognitive impairments.